The overall goal of this project is to deepen our understanding of aging processes and the aging brain in a community-based population. Our projects are thematically linked to an overarching hypothesis based on previous results from our own studies and the literature: that microinfarcts are key pathophysiological processes in late life brain dysfunction. Aims 1 & 2 will test hypotheses regarding 4 late-life brain outcomes: 1) Development of dementia and AD; 2) Trajectories of global cognitive decline incorporating sophisticated modern psychometric analyses; 3) Standard microscopic neuropathological measures; and 4) Novel biochemical neuropathological markers, including soluble A(S oligomers, markers of regional oxidative damage, and inflammatory markers. Aim 1. Exploit unique clinical records to test hypotheses about the association between mid- and late-life micro- and macro-vascular conditions and late-life brain outcomes. Aim 1 will take advantage of the >117,000 person-years of medical record data available from the cohort. Aim la. Test hypotheses related to type 2 diabetes (DM). We will identify the independent and joint contributions of mid-life and late-life insulin resistance and hyperglycemia on late-life brain outcomes to determine whether these outcomes are best explained by insulin resistance, hyperglycemia, or both. Aim lb. Test hypotheses related to renal disease. We will determine whether mid-life and late-life renal function is associated with greater risk for late-life brain outcomes. Aim 1c. Test hypotheses related to atrial fibrillation (AF). We will determine whether AF is associated with higher risk for late-life brain outcomes, whether increased persistence and duration of AF convey additional increased risk, and the extent to which anticoagulation ameliorates risks associated with AF. Aim 2. Exploit unique ACT study research data to test hypotheses about the association between late-life measures of physical performance, frailty, and late-life brain outcomes. We will follow-up our preliminary finding that timed walk during life is associated with the presence of microinfarcts among autopsied participants to more fully test the hypotheses that decrements in timed walk and the development of frailty precede late-life brain outcomes. Aim 3. Continue to serve as a valuable scientific resource and improve infrastructure to facilitate external use of ACT data.